Addition compounds of piperazinediones



2,887,474 Patented May 19, 1959 United States Patent "ice The foregoing reaction can be conveniently ettected by mixing at room temperature, the desired sarcosine anhydride compound and the substituted urea compound in the presence of an inert organic solvent with stirring until 5 the complex is formed, followed by filtering to recover the solid complex from the remaining liquids of the reaction mixture. Any inert organic solvent can be employed in the present invention and among those most useful are the lower aliphatic alcohols, the usual hydrocarbon and N9 Drawing- Application February 1957 10 ether solvents and, if desired, mixtures thereof.

Sena 639,220 The following specific examples are set forth for the 11 Claims. (Cl. 260-965) purpose of illustrating the present invention and should not be construed to limit the invention to the precise com- 5 ponents or proportions employed.

2,887,474 ADDITION COMPOUNDS 0F PIPERAZINEDIONES Arthur Alter, Waukegan, Harold E. Zaugg, Lake Forest, and Richard U. Schock, Waukegan, Ill., assignors to Abbott Laboratories, North Chicago, 111., a corporation of Illinois This invention relates to novel substituted 2,5-pipera- 1 zinediones-sarcosine anhydride-sustituted urea complexes EXAMPLE I and to the process for preparing these compounds.

The substituted piperazinediones-substituted urea com- S c sine anhydride (4,4-dinitradil y plexes of the present invention are distinct chemical comcomplex pounds having definite chemical and physical properties A mixtureof 3.0 grams (0.01 mole) of 4,4-dinitrodifiering from the individual components of the complex dlphenylguanidine, 2.1 g. (0.015 mole) of sarcosine anand are comprised in general of two moles of the subhydride and 20 ml. of methanol 1s stirred at room temstituted urea composition for each mole of sarcosine an- Perature for 6 hours. The solld product, 4,4'-dinitr& hydride d, diphenylguanidine-sarcosine anhydride complex, is fil- The compounds of the present invention are represented tered, Suspended 111 20 of methanol and again Stirredby the following general formula: The product is then filtered and washed with methanol.

The yield is 3.0 g.; M.P. 204-205".

X The product, sarcosine anhydride-(4,4'-dinitrodipl1enyl- 1| guanidine) complex, on chemical analysis is found to A NH NH- contain 51.65% C, 4.49% H, 22.25% N and 21.30% 0;

H as compared with a theoretical analysis of 51.7% C, 4.3%

40 H, 22.6% N and 0.

EXAMPLE H Sarcosine anhydride-(4,4'-dinitr0carbanilide) complex wherein R is a methyl group or a substituted methyl group, R is hydrogen, halogen or a lower alkyl group, A is a nitro, cyano, trimethyl ammonium, sulfamyl, sulfonic acid or other electron withdrawing group, X is A mixture of 18.0 g. (0.06 mole) of 4,4-dinitrocarbani- NH, 0, or S, and n is the integer 1 or 2.

The compounds of the present invention are prepared ml. of methanol are stirred for 16 hours. The product by reacting a substituted 2,5-piperazinedione compound is separated by filtration and washed liberally with methahaving the general formula: 1101. The product, sarcosine anhydride-di(4,4-dinitro- 0 carbanilide), after drying weighs 20.5 grams and melts at 285-6 C. with decomposition.

The said product on chemical analysis is found to con- 0 tain 51.6% C, 4.00% H, 19.00% N, 25.65% 0; as com pared to the theoretical analysis of 51.47% C, 4.05% H,

wherein R is a methyl group or a substituted methyl group, 18'76% 25'71% and R is hydrogen or a lower alkyl group, with a sub- EXAMPLE HI stituted urea compound having the general formula:

R, Sarcosine anyhdride-(4,4'-dinitrodiphenylthiourea) 2 complex A- NHONH A 0 wherein R is a lower alkyl group, A is anitro, cyano, cars ll N-CH-2 ON NHONH NO boxyl, carboalkoxy, acetyl, or other electron withdrawing a 2 2 group, and X is NH, O, or S. (i

lide, 5.7 g. (0.04 mole) of sarcosine anhydride and A mixture of 3.2 g. (0.01 mole) of 4,4'-dinitrodiphenlythiourea, 2.1 g. (0.015 mole) of sarcosine anhydride and 20 ml. of methanol are stirred for 6 hours. The product, sarcosine anhydride-di(4,4'-dinitrodiphenylthiourea), is filtered and washed with methanol. The product is obtained in a yield of 3.4 g. and has a M.P. of 210-211.

The said product on chemical analysis is found to contain 49.5% C, 4.1% H, 17.76% N, 20.97% 0, 9.01% S; as compared to the theoretical analysis 49.35% C, 3.88% H, 17.99% N, 20.54% 0, 8.23% S.

EXAMPLE IV Sarcosine anhydride-(4,4-dicyancarbanilide) complex 103,11 N 011 -2 ONQNHOOHNQON EXAMPLE V sarcosine anhydride-(4,4-disulfamylcarbanilide) complex 0 CH N A mixture of 4,4-disulfamylcarbanilide (3.7 g.) is stirred in 25 ml. methyl alcohol with 2.8 g. (0.02 M) sarcosine anhydride at room temperature for 8 hours. The solid complex product is filtered, washed with few cc. methyl alcohol, and dried in a vacuum oven. A yield of 4.8 g. of the said complex is obtained having a M.P. of 2534 C. On chemical analysis, the said complex is found to contain 44.79% C, 4.95% H, and 12.31% S; as compared with the theoretical analysis of 44.52% C, 4.72% H, and 12.51% S.

EXAMPLE VI Sarcosine anhydride-(4,4-dirzitro-2,2'- dichlorocarbanilia'e complex A mixture of 4,4'-dinitro-2,2'-dichlorocarbanilide (3.7 g.) and sarcosine anhydride (2.8 g.) is stirred at room temperature with 25 ml. methyl alcohol for 8 hours, The complex product is filtered, washed with a few cc. of methyl alcohol, pressed dry, and dried in a vacuum oven. A yield of 4.0 g. of the said complex is obtained having a M.P. of 280-1 C. On chemical analysis, the said complex is found to contain 43.39% C, 3.18% H, and 15.77% N; as compared with a theoretical analysis of 43.46% C, 2.96% H, and 15.84% N.

The sarcosine anhydride-substituted urea complexes of the present invention have shown marked activity against E. tenella and are useful for controlling the disease designated coccidiosis of which E. tenella is one of the chief causative agents and which is commonly found in chickens and other poultry. Accordingly, one practical 4 embodiment of the present invention is an ingestible poultry composition containing a small amount of a sarcosine anhydride-substituted urea complex of the present invention as the active-ingredient thereof. The said complex being relatively stable, high melting solid can be conveniently dispersed in an inert non-toxic carrier, either liquid dispersion or solid, and which can be safely administered to poultry. Any of the usual poultry feed compositions can be used as a carrier for the new complexes of the present invention, including mixtures containing ground corn meal, soybean meal, bone meal, limestone flour or water.

A typical poultry feed containing a complex of the present invention has the following composition:

It will be apparent that the complex of the present invention comprises about 0.0125 of the feed mixture.

For convenience of handling and for mixing the said complex into the poultry feed, it is desirable to prepare a pre-mix which contains between 5% and 50% by weight of the said complex, dispersed in a corn meal feed base or combination of other meals used to prepare the feed.

The complexes of the present invention are effective in the control of coccidiosis in poultry at very low concentrations and marked activity is evident when as little as 0.005% by wt. thereof, is incorporated in a poultry feed mixture. It is preferred, however, to use the complexes of the present invention at a level of almost 0.0125 by wt. in the complete poultry feed mix. Higher concentration up to about 0.1% by wt. can also be effectively used.

The following anticoccidial test data shows the effec- The procedure used to obtain the above data under conditions of severe challenge was to mix the specified test compound on the specified amounts in a standard chick starter diet, and start 7-day old chicks on the medicated feed. Twenty-four hours later the chicks were infected by gavage with 500,000 oocysts of E. tenella. This was designed to give a death rate of around 50% in untreated controls. The chicks were continued on the medicated feed continuously until 7 days post-treatment. Birds dying during the 7-day period were necropsied for evidence of coccidiosis. The survivors at the end of 7 days were all sacrificed and similarly examined,

The results with different dosages of the test compound are shown in Table I in terms of mortality rate in the 7-day period, the percent of the survivors showing lesions (at 7 days), and the average severity of the lesions. The average severity of the lesions is determined by examining each survivor for lesions which are rated as being absent, very light, light, medium, or heavy, and which are then given a numerical value of 0, 1, 2, 3, and 4, respectively. The sum of the numerical values of all survivors by the number of survivors gives the severity of lesions of Table I.

Others may readily adapt the invention for use under various conditions of service, by employing one or more of the novel features disclosed or equivalents thereof. As at present advised with respect to the apparent scope of our invention, we desire to claim the following subject matter.

We claim:

1. A compound having the general formula wherein R is a methyl group, R is selected from the group consisting of hydrogen, chlorine, and lower alkyl, X is selected from the group consisting of oxygen, sulfur and NH, A is an electron withdrawing group selected fiom the group consisting of a nitro, cyano, dimethylammonium, sulfamyl, and sulfonic acid groups, and n is an integer greater than 0 and less than 3.

2. A compound having the general formula 0 n R 3'; R-N N-Rm A Nnri-Nn- A wherein R is a methyl group, R is hydrogen, X is NH, A is a nitro group, and n is 2.

3. A compound having the general formula wherein R is a methyl group, R is hydrogen, X is oxygen, A is a nitro group, and n is 2.

4. A compound having the general formula wherein R is a methyl group, R is chlorine, X is oxygen, A is a nitro group, and n is 2.

References Cited in the file of this patent Cuckler et al.: Science, 122, pp. 244-5 (1955). 

1. A COMPOUND HAVING THE GENERAL FORMULA 